Glioblastomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority (~75%) of these tumors. Resistance to genotoxic modalities in p53-intact gliomas has been attributed to attenuation of p53 functions by other mutations within a p53 signaling axis that includes CDKN2A(p14 Arf), MDM2 and ATM. In preliminary studies, we have generated an alternative and potentially actionable resolution to the p53 paradox. Put briefly, we have shown that the gliogenic transcription factor OLIG2 suppresses p53-mediated responses to genotoxic damage in glioblastoma cells. Against this backdrop, the broad objective of studies proposed in this SPORE project is to use clinical materials to test the hypothesis that small molecule inhibitors of OLIG2 could serve as targeted therapeutics for glioblastoma - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs. This hypothesis makes four testable predictions: Our first specific aim is to test the prediction that current standard of care (radiation and Temozolomide) actually enriches for OLIG2-positive cells within p53-positive glioblastomas. Our second specific aim is to test the prediction that one current class of radiosensifizing drugs - the HDAC inhibitors - actually work by suppressing OLIG2 expression in cancer patients. Our third specific aim is to test the prediction that genetic suppression of OL1G2 can sensitize p53-positive human gliomas to radiotherapy in vivo. Our fourth specific aim is to test the prediction that shRNA-mediated knockdown of genes essential to OLIG2 function (e.g. HDACs) will be synthetic lethal to irradiation in p53 positive gliomas. The basic scientist on this project (CD Stiles, PhD) is a molecular biologist and the clinical investigator (JS Loeffler) is a radiation oncologist. Dr Stiles and his students initially cloned the OLIG genes and defined their biological functions in brain development and malignant glioma. Dr Loeffier is a leader in the field of brain tumor irradiation with a special interest in glioblastomas. Together they have the skill sets required for successful completion ofthe study plan. The work they propose will be supported by dedicated SPORE core facilities for Pathology and Biostatistics. If the work described here supports the view that OLIG2 is a viable target for glioma therapeutics, clinical trials of OLIG2 antagonists (e.g. HDAC inhibitors) as an adjuvant to radiotherapy can be initiated within a five-year period of time.